This invention pertains to a process for the preparation of compounds containing the fused heterocyclic pyrrolo[2,3-d]pyrimidine ring system which can be depicted as follows: ##STR1##
A variety of compounds containing this ring system have been described in the literature. 7-Deazaguanine is a pyrrolo[2,3-d]pyrimidine reported by Davoll, J. Chem. Soc., 1960, 131. The pyrrolo[2,3-d]pyrimidine ring also is found in queuine, the aglycon of queuosine, and in the N-[4-{3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl}benzoyl]glutam ic acid derivatives described in U.S. Pat. No. 4,997,838. 5-Aminoalkynylpyrrolo[2,3-d]pyrimidines are described in U.S. Pat. No. 5,047,519. Fluorescent dyes containing the pyrrolo[2,3-d]pyrimidine ring system are used as reagents to identify guanosine and adenosine terminators in the automated sequencing of DNA {See Cocuzza, Tetrahedron Left., 29, No. 33, 4061}. U.S. Pat. No. 5,344,932 describes N-[4-{2-(2-hydroxy-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl}benzoyl]g lutamic acid and related compounds as being antineoplastic agents (See also, Taylor et al., J. Med. Chem., 1992, 35, 4450). U.S. Pat. Nos. 4,996,206, 5,028,608, and 5,248,775 describe other antineoplastic agents which also have the pyrrolo[2,3-d]pyrimidine ring system.
Typically in these compounds, the 2-position of the pyrrolo[2,3-d]pyrimidine ring will be unsubstituted or substituted with amino, but alternatively can carry an unsubstituted or substituted group such as alkyl, aralkyl, aryl, alkylthio, aralkylthio, or arylthio. The 4-position of the pyrrolo[2,3-d]pyrimidine ring generally will carry an oxo or amino group. (It will be appreciated that the 4(3H)-oxopyrrolo[2,3-d]pyrimidine and 4(3H)-iminopyrrolo[2,3-d]pyrimidine structures are the tautomeric equivalents of the 4-hydroxypyrrolo[2,3-d]pyrimidine and 4-aminopyrrolo[2,3-d]pyrimidine structures, respectively). The principal points of structural variation generally involve the 5- and 7-positions of the pyrrolo[2,3-d]pyrimidine structure, that is, the second carbon atom from the ring nitrogen atom of the pyrrole ring and the ring nitrogen atom itself of the pyrrole ring, respectively.
Substitution of the nitrogen atom in the 7-position generally does not pose a serious problem. Introducing a substituent in the 5-position, however, is considerably more problematical. One synthetic approach involves synthesizing the pyrrolo[2,3-d]pyrimidine system and then coupling this, typically as a 5-halo derivative, with a reagent carrying a precursor for the substituent in the 5-position. See e.g. Cocuzza, supra, and U.S. Pat. No. 5,344,932. This route requires synthesis of the 5-substituted pyrrolo[2,3-d]pyrimidine intermediates, which often is difficult, as well as the performance of a number of synthetic steps subsequent to coupling.
An alternative approach involves constructing the pyrrolo[2,3-d]pyrimidine ring through cyclization, as for example, allowing an .alpha.-dicyanomethyl derivative of a substituted alkanoic acid ester to react with guanidine. See e.g. U.S. Pat. No. 4,997,838.
Yet a further approach involves the reaction of a nucleophile of the formula R.sup.2 -C(.dbd.NH)NH.sub.2 and a 2-amino-5-substituted-furan carrying a cyano or carboxy group in the 4-position, as described for example in U.S. Pat. No. 5,254,687, Taylor et al., J. Org. Chem., 60, 6684 (1995), and Taylor et al., J. Org. Chem, 61, 7973 (1996). For example ethyl 4{2-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)-ethyl}benzoate, an intermediate for the preparation of the known N-[4-{2-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)ethyl}benzoyl]-L-glutamic acid, is prepared by allowing guanidine and ethyl 4-[2-(2-amino-3-cyanofur-4-yl)ethyl]benzoate to react under mild conditions. The known N-[4-{3-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)propyl}benzoyl]-L-glutami c acid is similarly prepared from methyl 4-[3-(2-amino-3-cyanofur-4-yl)propyl]benzoate.
The present invention involves a new process for preparing pyrrolo[2,3-d]pyrimidine compounds that is direct, inexpensive, and capable of broad applicability. The process permits synthesis of a wide variety of 7H-pyrrolo[2,3-d]pyrimidines, including but not limited to those described in U.S. Pat. Nos. 5,344,932, 5,254,687, 4,996,206, 5,028,608, and 5,248,775, that are substituted in the 5-position. In the present process, the 5-substituent (designated herein as "R") is "pendant" and not involved in any way in the formation of the bicyclic structure so that it can be varied widely in carbon content and structure.